The prognosis, chemotherapy and immunotherapy efficacy of the SUMOylation pathway signature and the role of UBA2 in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is one of the most common malignant tumors worldwide. Small Ubiquitin-like Modifier (SUMO)-ylation plays a crucial role in tumorigenesis. However, the SUMOylation pathway landscape and its clinical implications in LUAD remain unclear. Here, we analyzed genes involved in the SUMOylation pathway in LUAD and constructed a SUMOylation pathway signature (SUMOPS) using the LASSO-Cox regression model, validated in independent cohorts. Our analysis revealed significant dysregulation of SUMOylation-related genes in LUAD, comprising of favorable or unfavorable prognostic factors. The SUMOPS model was associated with established molecular and histological subtypes of LUAD, highlighting its clinical relevance. The SUMOPS stratified LUAD patients into SUMOPS-high and SUMOPS-low subtypes with distinct survival outcomes and adjuvant chemotherapy responses. The SUMOPS-low subtype showed favorable responses to adjuvant chemotherapy. The correlations between SUMOPS scores and immune cell infiltration suggested that patients with the SUMOPS-high subtype exhibited favorable immune profiles for immune checkpoint inhibitor (ICI) treatment. Additionally, we identified UBA2 as a key SUMOylation-related gene with an increased expression and a poor prognosis in LUAD. Cell function experiment confirmed the role of UBA2 in promoting LUAD cell proliferation, invasion, and migration. These findings provide valuable insights into the SUMOylation pathway and its prognostic implications in LUAD, paving the way for personalized treatment strategies and the development of novel therapeutic targets.

Prognostic and chemotherapeutic response prediction by proliferation essential gene signature: Investigating POLE2 in bladder cancer progression and cisplatin resistance.

Background: Bladder cancer (BLCA) is the most common genitourinary malignancy. Proliferation essential genes (PEGs) are crucial to the survival of cancer cells. This study aimed to build a PEG signature to predict BLCA prognosis and treatment efficacy. Methods: BLCA PEGs and differentially expressed PEGs were identified using DepMap and TCGA-BLCA datasets, respectively. Based on the prognostic analysis of the differentially expressed PEGs, a PEG model was constructed. Subsequently, we analyzed the relationship between the PEG signature and prognosis of BLCA patients as well as their response to chemotherapy. Finally, we performed random forest analysis to target and functional experiments to validate the most significant PEG which is associated with BLCA progression. CCK-8, invasion, migration, and chemosensitivity assays were performed to assess effects of gene knockdown on BLCA cell proliferation, invasion and migration abilities, and cisplatin chemosensitivity. Results: We screened 10 prognostic PEGs from 201 differentially expressed PEGs and used them to construct a PEG signature model. Patients with high PEG signature score (PEGs-high) exhibited worse OS and lower sensitivity to chemotherapy than those with PEGs-low. We also found significant correlations between the PEG score and previously defined BLCA molecular subtypes. This suggests that the PEG score may effectively predict the molecular subtypes which have distinct clinical outcomes. Random forest analysis revealed that POLE2 (DNA polymerase epsilon subunit 2) was the most significant PEG differentiating BLCA tissue and normal tissue. Bioinformatic analysis and an immunohistochemistry staining assay confirmed that POLE2 was significantly up-regulated in tumor tissues and was associated with poor survival in BLCA patients. Moreover, POLE2 knockdown inhibited the ability of cell clone formation, proliferation, invasion, immigration and IC50 of cisplatin. Conclusion: The PEG signature acts as a potential predictor for prognosis and chemotherapy response in BLCA patients. POLE2 is a key PEG and plays a remarkable role in promoting the malignant progression and cisplatin resistance of BLCA.

Single-cell multi-omics in the study of digestive system cancers.

Digestive system cancers are prevalent diseases with a high mortality rate, posing a significant threat to public health and economic burden. The diagnosis and treatment of digestive system cancer confront conventional cancer problems, such as tumor heterogeneity and drug resistance. Single-cell sequencing (SCS) emerged at times required and has developed from single-cell RNA-seq (scRNA-seq) to the single-cell multi-omics era represented by single-cell spatial transcriptomics (ST). This article comprehensively reviews the advances of single-cell omics technology in the study of digestive system tumors. While analyzing and summarizing the research cases, vital details on the sequencing platform, sample information, sampling method, and key findings are provided. Meanwhile, we summarize the commonly used SCS platforms and their features, as well as the advantages of multi-omics technologies in combination. Finally, the development trends and prospects of the application of single-cell multi-omics technology in digestive system cancer research are prospected.

Transcriptomics and metabolomics association analysis revealed the responses of Gynostemma pentaphyllum to cadmium.

Gynostemma pentaphyllum an important medicinal herb, can absorb high amounts of cadmium (Cd) which can lead to excessive Cd contamination during the production of medicines and tea. Hence, it is crucial to investigate the response mechanism of G. pentaphyllum under Cd stress to develop varieties with low Cd accumulation and high tolerance. Physiological response analysis, transcriptomics and metabolomics were performed on G. pentaphyllum seedlings exposed to Cd stress. Herein, G. pentaphyllum seedlings could significantly enhance antioxidant enzyme activities (POD, CAT and APX), proline and polysaccharide content subject to Cd stress. Transcriptomics analysis identified the secondary metabolites, carbohydrate metabolism, amino acid metabolism, lipid metabolism, and signal transduction pathways associated with Cd stress, which mainly involved the XTH, EXP and GST genes. Metabolomics analysis identified 126 differentially expressed metabolites, including citric acid, flavonoid and amino acids metabolites, which were accumulated under Cd stress. Multi-omics integrative analysis unraveled that the phenylpropanoid biosynthesis, starch, and sucrose metabolism, alpha-linolenic acid metabolism, and ABC transporter were significantly enriched at the gene and metabolic levels in response to Cd stress in G. pentaphyllum. In conclusion, the genetic regulatory network sheds light on Cd response mechanisms in G. pentaphyllum.

Association between periodontal disease and oral squamous cell carcinoma: a systematic review and meta-analysis.

To investigate the relation between periodontal disease (PD) and oral squamous cell carcinoma (OSCC) we systematically searched records published up to August 2022. Odds ratios (OR) and relative risk (RR) with 95% confidence intervals (95% CI) were estimated to evaluate this relation, then sensitivity analysis was performed accordingly. Begg's test and Egger's test were used to detect publication bias. Out of 970 papers from several databases, 13 studies were included. Summary estimates showed that PD was positively associated with the prevalence of OSCC (OR = 3.28, 95% CI: 1.87 to 5.74), especially for severe PD (OR = 4.23, 95% CI: 2.92 to 6.13). No evident publication bias was revealed. No increased OSCC risk among patients with PD was shown according to the combined results (RR = 1.50, 95% CI: 0.93 to 2.42). Patients with OSCC exhibited significant differences in alveolar bone loss, clinical attachment loss, and bleeding on probing, when compared with controls. The systematic review and meta-analysis suggested that there was a positive association between PD and prevalence of OSCC. However, according to the current evidence, a causal relation is unclear.

WIPI2 enhances the vulnerability of colorectal cancer cells to erastin via bioinformatics analysis and experimental verification.

Introduction: WD Repeat Domain Phosphoinositide Interacting 2 (WIPI2) is a WD repeat protein that interacts with phosphatidylinositol and regulates multiprotein complexes by providing a b-propeller platform for synchronous and reversible protein-protein interactions assembled proteins. Ferroptosis is a novel iron-dependent form of cell death. It is usually accompanied with the accumulation of membrane lipid peroxides. Our study is to focus on investigating the effect of WIPI2 on the growth and ferroptosis of colorectal cancer (CRC) cells and its potential mechanism. Methods: We analyzed the expression of WIPI2 in colorectal cancer versus normal tissues through The Cancer Genome Atlas (TCGA), and the relationship between clinical traits and WIPI2 expression and prognosis was assessed by univariate and multifactorial cox analysis. Next, we constructed the siRNAs targeting the WIPI2 sequence si-WIPI2 to further investigate the mechanism of WIPI2 in CRC cells through vitro experiments. Results: Public data from the TCGA platform showed that WIPI2 expression was significantly elevated in colorectal cancer tissues compared to paracancerous tissues, and high WIPI2 expressionpredicted poor prognosis for CRC patients. Moreover, we found that the knockdown of WIPI2 expression could inhibit the growth and proliferation of HCT116 and HT29 cells. Furthermore, we found that the expression level of ACSL4 decreased and that of GPX4 increased when WIPI2 was knocked down, suggesting that WIPI2 can potentially positively regulate CRC ferroptosis. Meanwhile, both NC and si groups were able to further inhibit cell growth activity, as well as increase WIPI2 and decrease GPX4 expression when treated with Erastin, but the rate of cell viability inhibition and the trend of protein changes were more significantly in the NC group than si groups, which indicated that Erastin induced CRC ferroptosis through the WIPI2/GPX4 pathway thereby enhancing the sensitivity of colorectal cancer cells to Erastin. Conclusions: Our study suggested that WIPI2 had a promotional effect on the growth of colorectal cancer cells, and it also played an important role in the ferroptosis pathway.

Cultivable endophytic fungal community associated with the karst endemic plant Nervilia fordii and their antimicrobial activity.

Endophytic fungi from medicinal plants with specific pharmacological functions attract much attention to provide the possibility of discovering valuable natural drugs with novel structures and biological activities. Nervilia fordii is a rare and endangered karst endemic plant that is used as medicine and food homology in Guangxi, China. These plants have been reported to have antimicrobial, antitumor, antiviral, and anti-inflammatory activities. However, few studies have focused on the diversity and antibacterial activity of endophytic fungi from N. fordii. In the present study, 184 endophytic fungi were isolated from the healthy tissues of N. fordii, and their molecular diversity and antimicrobial activities were analyzed for the first time. These fungi were categorized into 85 different morphotypes based on the morphological characteristics and the similarity between the target sequence and the reference sequence in the GenBank database. With the exception of 18 unidentified fungi, the fungal isolates belonged to at least 2 phyla, 4 classes, 15 orders, 45 known genera, and 45 different species, which showed high abundance, rich diversity, and obvious tissue specificity. All isolates were employed to screen for their antimicrobial activities via the agar diffusion method against Escherichia coli, Staphylococcus aureus, and Candida tropicalis. Among these endophytes, eight strains (9.41%) displayed inhibitory activity against E. coli, 11 strains (12.94%) against S. aureus, and two strains (2.35%) against C. tropicalis, to some extent. In particular, our study showed for the first time that the fungal agar plugs of Penicillium macrosclerotiorum 1151# exhibited promising antibacterial activity against E. coli and S. aureus. Moreover, the ethyl acetate (EA) extract of P. macrosclerotiorum 1151# had antibacterial effects against E. coli and S. aureus with a minimum inhibitory concentration (MIC) of 0.5 mg ml-1. Further research also confirmed that one of the antimicrobial compounds of P. macrosclerotiorum 1151# was methyl chloroacetate and exhibited excellent antibacterial activity against E. coli and S. aureus up to 1.71-fold and 1.13-fold compared with tetracycline (TET) (5 mg ml-1), respectively. Taken together, the present data suggest that various endophytic fungi of N. fordii could be exploited as sources of novel natural antimicrobial agents.

Rapid differentiation of hiPSCs into functional oligodendrocytes using an OLIG2 synthetic modified messenger RNA.

Transcription factors (TFs) have been introduced to drive the highly efficient differentiation of human-induced pluripotent stem cells (hiPSCs) into lineage-specific oligodendrocytes (OLs). However, effective strategies currently rely mainly on genome-integrating viruses. Here we show that a synthetic modified messenger RNA (smRNA)-based reprogramming method that leads to the generation of transgene-free OLs has been developed. An smRNA encoding a modified form of OLIG2, in which the serine 147 phosphorylation site is replaced with alanine, OLIG2S147A, is designed to reprogram hiPSCs into OLs. We demonstrate that repeated administration of the smRNA encoding OLIG2 S147A lead to higher and more stable protein expression. Using the single-mutant OLIG2 smRNA morphogen, we establish a 6-day smRNA transfection protocol, and glial induction lead to rapid NG2+ OL progenitor cell (OPC) generation (>70% purity) from hiPSC. The smRNA-induced NG2+ OPCs can mature into functional OLs in vitro and promote remyelination in vivo. Taken together, we present a safe and efficient smRNA-driven strategy for hiPSC differentiation into OLs, which may be utilized for therapeutic OPC/OL transplantation in patients with neurodegenerative disease.

Active meiosis during dinoflagellate blooms: A 'sex for proliferation' hypothesis.

In dinoflagellates, sexual reproduction is best known to be induced by adverse environmental conditions and culminate in encystment for survival ('sex for encystment'). Although increasing laboratory observations indicate that sex can lead to production of vegetative cells bypassing encystment, the occurrence of this alternative pathway in natural populations and its ecological roles remain poorly understood. Here we report evidence that sex in dinoflagellates can potentially be an instrument for bloom proliferation or extension. By bloom metatranscriptome profiling, we documented elevated expression of meiosis genes in two evolutionarily distinct species (Prorocentrum shikokuense and Karenia mikimotoi) during bloom, a timing unexpected of the 'sex for encystment' scenario. To link these genes to meiosis, we induced encystment and cyst germination in the cyst-forming species Scrippsiella acuminata, and found that five of these genes were upregulated during cyst germination, when meiosis occurs. Integrating data from all three species revealed that SPO11, MND1, and DMC1 were likely common between cyst-forming and non-encysting sex in dinoflagellates. Furthermore, flow cytometric analyses revealed consecutive rounds of DNA halving during blooms of P. shikokuense and K. mikimotoi, evidencing meiosis. These data provided novel evidence that sexual reproduction in dinoflagellates might serve to promote cell proliferation, and along with the consequent enhancement of genetic diversity facilitating resistance against pathogens and environmental stress, to boost or extend a bloom ('sex for proliferation'). The putative meiosis-specific genes and insights reported here will prove to be helpful for rigorously testing the hypothesis and addressing whether the two modes of sex are genetically predisposed (i.e. species-specific) or environmentally induced (switchable within species), and if the latter what triggers the switch.

IL-34 was high in serum of women with polycystic ovary syndrome and may function as potential diagnostic biomarker and therapeutic target.

BACKGROUND: Polycystic ovary syndrome (PCOS) is one of the most prevalent endocrine disorders in females of reproductive age, with a prevalence of 20%-33% in the general population. Interleukin (IL)-34 is a recently explored proinflammatory cytokine and is an important modulator in different disease types. However, the function of IL-34 in PCOS has yet to be investigated. OBJECTIVE: The purpose of this study was to determine the IL-34 serum level in women with PCOS and to compare it to that of a relatively healthy control group. Focusing on its relationship with IL-6, TNF-α, and IL-1ß and homeostatic model assessment for insulin resistance (HOMA-IR), triglyceride, and low-density lipoprotein cholesterol (LDL-C). MATERIALS AND METHODS: In this study, blood samples were obtained from 100 women with PCOS and 100 healthy control women for the purpose of estimating their serum levels of IL-34, IL-6, TNF-α, and IL-1ß using the enzyme-linked immunosorbent assay technique. RESULTS: Serum levels of IL-34, IL-6, TNF-α, and IL-1ß were all higher in PCOS women than in healthy controls, and the difference was highly statistically significant. Serum IL-34 concentration was positively correlated with IL-6, TNF-α, and IL-1ß concentration. Additionally, serum concentrations of IL-34 were positively correlated with HOMA-IR, triglyceride, and LDL-C. CONCLUSION: When compared to normal women, IL-34, IL-6, TNF-α, and IL-1ß levels were highly statistically significant in PCOS, and these high levels were associated with other cytokines (IL-6, TNF-α, and IL-1ß), HOMA-IR, triglyceride, and LDL-C.

Exonic variants undergoing allele-specific selection in cancers.

BACKGROUND: Allelic imbalance (AI) in tumors is caused by chromosomal and sub-chromosomal gains and losses. RESULTS: We evaluated AI at 109,086 germline exonic SNP loci in four cancer types, and identified a set of SNPs that demonstrate strong tumor allele specificity in AI events. Further analyses demonstrated that these alleles show consistently different frequencies in the cancer population compared to the healthy population and are significantly enriched for predicted protein-damaging variants. Moreover, genes harboring SNPs that demonstrate allele specificity are enriched for cancer-related biological processes and are more likely to be essential in cancer cells. CONCLUSIONS: In summary, our study provides a unique and complementary method to identify genes and variants that are relevant to carcinogenesis.

Small-Molecule Inhibitors of the RNA M6A Demethylases FTO Potently Support the Survival of Dopamine Neurons.

The fat mass and obesity-associated protein (FTO), an RNA N6-methyladenosine (m6A) demethylase, is an important regulator of central nervous system development, neuronal signaling and disease. We present here the target-tailored development and biological characterization of small-molecule inhibitors of FTO. The active compounds were identified using high-throughput molecular docking and molecular dynamics screening of the ZINC compound library. In FTO binding and activity-inhibition assays the two best inhibitors demonstrated Kd = 185 nM; IC50 = 1.46 µM (compound 2) and Kd = 337 nM; IC50 = 28.9 µM (compound 3). Importantly, the treatment of mouse midbrain dopaminergic neurons with the compounds promoted cellular survival and rescued them from growth factor deprivation induced apoptosis already at nanomolar concentrations. Moreover, both the best inhibitors demonstrated good blood-brain-barrier penetration in the model system, 31.7% and 30.8%, respectively. The FTO inhibitors demonstrated increased potency as compared to our recently developed ALKBH5 m6A demethylase inhibitors in protecting dopamine neurons. Inhibition of m6A RNA demethylation by small-molecule drugs, as presented here, has therapeutic potential and provides tools for the identification of disease-modifying m6A RNAs in neurogenesis and neuroregeneration. Further refinement of the lead compounds identified in this study can also lead to unprecedented breakthroughs in the treatment of neurodegenerative diseases.

Application of a simple skin stretching system and negative pressure wound therapy in repair of complex diabetic foot wounds.

The management of complex diabetic foot wounds with large skin defects poses a challenge for surgeons. We presented a simple skin stretching system and negative pressure wound therapy for the repair of complex diabetic foot wounds to examine the effectiveness and safety.A total of 16 patients with diabetic foot ulcers were retrospectively reviewed between January 2015 and October 2020. All patients underwent the treatment by 3 stages. In stage 2, these difficult-to-close wounds of diabetes foot were residual. This method was applied to the wounds with a median defect size of 20.42 cm2 (range, 4.71-66.76 cm2).The median time for closure of complex diabetic foot wounds was 14 days ranging from 8 to 19 days. With respect to the absolute rates of reduction, it was observed with a median of 1.86 cm2/day, ranging from 0.29 cm2/day to 8.35 cm2/day. In accordance with the localization of the defect, the patients were divided into 3 groups: side of the foot (37.5%), dorsum of the foot (50.0%), and others (12.5%). There was no statistical difference between side of the foot and dorsum of the foot in terms of the median defect size with P = 0.069 (Kruskal-Wallis test). Otherwise, there were statistically significant differences regarding the median time and the median absolute rates (P < 0.05; Kruskal-Wallis test). No severe complications were encountered in this study.In summary, our results show that application of the simple skin stretching system and NPWT is an effective and safe approach to complex diabetic foot wounds. Nevertheless, more attention should be paid to the appropriate patient selection and intraoperative judgment to ensure wound closure and avoid undue complications.

Ultrahigh Efficiency and Minimalist Intracellular Delivery of Macromolecules Mediated by Latent-Photothermal Surfaces.

Intracellular delivery of exogenous macromolecules by photothermal methods is still not widely employed despite its universal and clear effect on cell membrane rupture. The main causes are the unsatisfactory delivery efficiency, poor cell activity, poor cell harvest, and sophisticated operation; these challenges stem from the difficulty of simply controlling laser hotspots. Here, we constructed latent-photothermal surfaces based on multiwall carbon nanotube-doped poly(dimethyl siloxane), which can deliver cargoes with high delivery efficiency and cell viability. Also, cell release and harvest efficiencies were not affected by coordinating the hotspot content and surface structure. This system is suitable for use with a wide range of cell lines, including hard-to-transfect types. The delivery efficiency and cell viability were shown to be greater than 85 and 80%, respectively, and the cell release and harvest efficiency were greater than 95 and 80%, respectively. Moreover, this system has potential application prospects in the field of cell therapy, including stem cell neural differentiation and dendritic cell vaccines.

Netrin-1 and its receptor DCC modulate survival and death of dopamine neurons and Parkinson's disease features.

The netrin-1/DCC ligand/receptor pair has key roles in central nervous system (CNS) development, mediating axonal, and neuronal navigation. Although expression of netrin-1 and DCC is maintained in the adult brain, little is known about their role in mature neurons. Notably, netrin-1 is highly expressed in the adult substantia nigra, leading us to investigate a role of the netrin-1/DCC pair in adult nigral neuron fate. Here, we show that silencing netrin-1 in the adult substantia nigra of mice induces DCC cleavage and a significant loss of dopamine neurons, resulting in motor deficits. Because loss of adult dopamine neurons and motor impairments are features of Parkinson's disease (PD), we studied the potential impact of netrin-1 in different animal models of PD. We demonstrate that both overexpression of netrin-1 and brain administration of recombinant netrin-1 are neuroprotective and neurorestorative in mouse and rat models of PD. Of interest, we observed that netrin-1 levels are significantly reduced in PD patient brain samples. These results highlight the key role of netrin-1 in adult dopamine neuron fate, and the therapeutic potential of targeting netrin-1 signaling in PD.

Design, synthesis and antitumor activity of novel thiophene-pyrimidine derivatives as EGFR inhibitors overcoming T790M and L858R/T790M mutations.

Five series of novel thiophene-pyrimidine derivatives (9a-h, 10a-f, 11a-f, 12a-f, 13a-f) have been synthesized and tested for their anti-proliferative activity against several cancer cell lines in which EGF is highly expressed. Most of the target compounds showed excellent activity against one or more cancer cell lines. The most promising compound 13a, of which IC50 values on of cell lines A549 and A431 (4.34 ± 0.60 µM and 3.79 ± 0.57 µM) were similar to the lead compound Olmutinib, showed strong activity and selectivity to EGFRT790M and EGFRT790M/L858R. Inhibition data of human normal hepatoma cell line LO2 indicated that most target compounds were less toxic to normal cells and had selective inhibitory effects on cancer cells. In addition, the structure-activity relationship was analyzed and the mechanism of apoptosis induced by the 13a was studied. The results showed that compound 13a induced late apoptosis of A431 cancer cells in a dose-dependent manner.

RNA-seq profiling of Fugacium kawagutii reveals strong responses in metabolic processes and symbiosis potential to deficiencies of iron and other trace metals.

A healthy symbiotic relationship between corals and Symbiodiniaceae relies on suitable temperature and adequate nutrients including trace metals. Besides global warming, trace metal deficiency has been shown to cause coral bleaching, a phenomenon responsible for extensive coral reef degradation around the world. How trace metal deficiency impacts Symbiodiniaceae and coral symbiosis is poorly understood, however. In this study, we applied RNA-seq to investigate how Fugacium kawagutii responds to the deficiency of five trace metals (Fe2+, Zn2+, Cu2+, Mn2+, Ni2+). We identified 685 to 2805 differentially expressed genes (DEGs) from these trace metal deficiency conditions, among which 372 were commonly regulated by all the five trace metals and were significantly enriched in energy metabolism (e.g. fatty acid synthesis). Furthermore, genes associated with extracellular matrix (ECM), cell surface structure and cell adhesion were impacted, suggesting that the ability of recognition and adhesion of F. kawagutii may be altered by trace metal deficiencies. In addition, among the five metals, Fe2+ deficiency exhibited the strongest influence, with Fe-rich redox elements and many antioxidant synthesis genes being markedly down-regulated, indicative of adaptive reduction of Fe demand but a compromised ability to combat oxidative stress. Overall, deficiency of trace metals (especially Fe) seems to repress growth and ability of ROS scavenging, elevate energy metabolism and innate immunity, and alter cell adhesion capability, with implications in symbiosis disruption and coral bleaching.

Antioxidative CXXC Peptide Motif From Mesencephalic Astrocyte-Derived Neurotrophic Factor Antagonizes Programmed Cell Death.

Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a potent survival-promoting protein with neurorestorative effect for neurodegenerative diseases. Its mechanism of action, albeit poorly known, depends strongly on the CXXC motif (CKGC). Here we studied the survival-promoting properties of the CKGC tetrapeptide from MANF. In the Jurkat T lymphocytic cell line, CKGC potently inhibits death receptor Fas-induced apoptosis and mildly counteracts mitochondrial apoptosis and necroptosis. The peptide with serines instead of cysteines (SKGS) has no survival-promoting activity. The cytoprotective efficiency of the peptide against Fas-induced apoptosis is significantly improved by reduction of its cysteines by dithiotreitol, suggesting that it protects the cells via cysteine thiol groups, partially as an antioxidant. CKGC neutralizes the reactive oxygen species, maintains the mitochondrial membrane potential and prevents activation of the effector caspases in the Jurkat cells with activated Fas. The peptide does not require intracellular administration, as it is endocytosed and resides mainly in the Golgi. Finally, the peptide also potently promotes survival of cultured primary dopaminergic neurons.

Germline and somatic variations influence the somatic mutational signatures of esophageal squamous cell carcinomas in a Chinese population.

BACKGROUND: Esophageal squamous cell carcinomas (ESCC) is the fourth most lethal cancer in China. Previous studies reveal several highly conserved mutational processes in ESCC. However, it remains unclear what are the true regulators of the mutational processes. RESULTS: We analyzed the somatic mutational signatures in 302 paired whole-exome sequencing data of ESCC in a Chinese population for potential regulators of the mutational processes. We identified three conserved subtypes based on the mutational signatures with significantly different clinical outcomes. Our results show that patients of different subpopulations of Chinese differ significantly in the activity of the "NpCpG" signature (FDR = 0.00188). In addition, we report ZNF750 and CDC27, of which the somatic statuses and the genetic burdens consistently influence the activities of specific mutational signatures in ESCC: the somatic ZNF750 status is associated with the AID/APOBEC-related mutational process (FDR = 0.0637); the somatic CDC27 copy-number is associated with the "NpCpG" (FDR = 0.00615) and the AID/APOBEC-related mutational processes (FDR = 8.69 × 10- 4). The burdens of germline variants in the two genes also significantly influence the activities of the same somatic mutational signatures (FDR < 0.1). CONCLUSIONS: We report multiple factors that influence the mutational processes in ESCC including: the subpopulations of Chinese; the germline and somatic statuses of ZNF750 and CDC27 and exposure to alcohol and tobacco. Our findings based on the evidences from both germline and somatic levels reveal potential genetic regulators of the somatic mutational processes and provide insights into the biology of esophageal carcinogenesis.

Theoretical design and investigation of 1,8-naphthalimide-based two-photon fluorescent probes for detecting cytochrome P450 1A with separated fluorescence signal.

As a type of enzyme with a terminal oxygen, the CYP1A subfamily possesses the ability to catalyze the reactions of many environmental toxins, endogenous substrates and clinical drugs. The development of efficient methods for the rapid and real-time detection of CYP1A enzyme activity in complex biological systems is of considerable significance for identifying potential abnormalities in these cancer-related enzymes. With this goal, we firstly provided a series of 1,8-naphthalimide-based two-photon fluorescent chromophores with large two-photon absorption (TPA) cross-sections (500-7000 GM) and remarkable changes in fluorescence spectra upon recognizing the CYP1A enzyme from its theoretical aspect. Moreover, we have thoroughly studied the effects of cyclic acceptor (dichlorobenzene and benzothiadiazole) and donor (fluorene and carbazole) groups on the one-photon absorption (OPA), TPA, and fluorescence properties of CYP1A enzyme probes and the corresponding reaction products. The connection of a heterocycle as the donor group to a 1,8-naphthalimide-based molecule to form a D-π-A-π-D-type electronic structure can effectively cause red shifts in the absorption and emission wavelengths to facilitate bioimaging in the near infrared (NIR) region, which is attributed to the lower transition energy, larger transition dipole moment and amount of transferred charge. Docking analysis suggests that the two-photon fluorescent probes NCMN-3 and NCMN-5 that were designed will guarantee and achieve excellent selectivity for the CYP1A enzyme.